Peptic ulcer is a common disease, with the disease incidence in different areas at different stages being different, and it is about 10-20% of the number of total population generally. With social development and the change of lifestyle of people, the disease incidence of peptic ulcer caused by smoking, drinking, emotional stress, pharmaceutical stimulation and the like is gradually increased, which is seriously affecting work and life of the people. The exact pathogenesis is still not clear in the field of medicine at present, but inhibition of gastric acid secretion has been recognized as a preferred method for treating such diseases.
Since the first proton pump inhibitor (PPI) came into the market in 1988, there have been a number of PPI products coming into the market up to now. After years of clinical application, PPIs have been the preferred medicaments for treating gastric acid-related diseases. A proton pump, also called a gastric acid pump, is H adenosine triphosphatase (H+/K+-ATPase) essentially, is a final common pathway of gastric secretion of H exists on cell membranes of secretory tubules of gastric parietal cells and can perform H+ and K+ exchange by means of ATP degradation and specifically pump H+ into gastral cavity to form a strong acidic state in the stomach. The proton pump is a heterodimer and consists of transmembrane a and subunits. The a subunit has 10 helical transmembrane segments (M1-M10), is mainly responsible for catalytic activity of an enzyme and supply of ATP binding sites which are also binding sites for cations, and is also called a catalytic subunit; and the functional expression of the enzyme needs the participation of the single-pass transmembrane subunit. PPIs are weak alkaline and lipophilic compounds, can rapidly pass through the cell membranes of the gastric wall, are accumulated in the strong acidic secretory tubules, are converted to sulfonamide compounds under the catalytic action of H+, and are covalently bound to sulfhydryl on cysteine residues of an H+/K+-ATPase transmembrane region to form disulfide bonds, thereby inactivating the proton pumps and further inhibiting central or peripheral mediated gastric acid secretion.
The first generation of PPIs has an obvious effect of inhibiting gastric acid secretion stimulated by basic and nocturnal gastric acid, pentagastrin, test meal and the like. However, due to the limitations of pharmacokinetics and pharmacodynamics, including the effects of bioavailability and drug administration time on drug effects, slow onset of action of nocturnal acid breakthrough, instability in acidic conditions (the PPIs often need to be prepared into bowel preparations, and in such situations, the effects can only be seen after several hours), dependence on a CYP450 enzyme (the plasma concentrations of the PPIs of different patients are greatly different, which may cause great differences in acid inhibition effects of the different patients) and other factors, the treatment effects and the clinical application are affected. Compared with the first generation of PPIs, the new generation of PPIs has obvious advantages in treatment of gastroesophageal reflux disease (GERD) and other acid-related diseases.
As a novel type of acid inhibitors, potassium-competitive acid blockers (P-CABs) can inhibit the activity of the H+/K+-ATPase by competitively binding of H+, and the mechanism of action is obviously different from that of PPIs, so that the P-CABs may be called acid pump blockers. The P-CABs have the characteristics of lipophilicity, weak alkalinity, high dissociation constant and stability at low pH value. In an acidic environment, the P-CABs are immediately ionized, the ionized form is to inhibit the H+/K+-ATPase by ionic binding and prevent H+ transportation and acid secretion into the gastral cavity, the activation of microcapsules, microtubules and the acid concentrated on gastric parietal cells is not required, the pH value in the stomach can be rapidly increased, and the enzymatic activity after dissociation is recovered. Rapid absorption can be realized after oral administration to human and animals, and the peak plasma concentrations can be achieved. Clinical and animal experiments also show that, compared with the PPIs or the H2 receptor blockers, the P-CABs are faster in onset of action and stronger in the action of increasing the pH, wherein part of the P-CABs preparations have entered phase II and phase III clinical researches. The P-CABs have the following potential advantages: rapid onset of action, wherein the maximum effect can be achieved within 1 h; and linear correlation between plasma concentration and oral administration dosage, suggesting that such medicaments can achieve the best acid inhibition state relatively easily.
At present, a series of patent applications of potassium-competitive acid blockers (P-CABs) are disclosed, wherein the patent applications comprise WO2005041961, WO2006134460, WO2009041447 or WO2010021149 and the like.
Although a series of potassium-competitive acid blockers (P-CABs) have been disclosed at present, novel compounds with better drug effects still need to be developed, and after continuous efforts, in the present invention, compounds represented by formula (I) are designed and it is found that a compound with such a structure exhibits excellent effect and function.